Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria

Alessandro S. de Sa Pinheiro; Douglas E. Teixeira; Rodrigo P. Silva-Aguiar; Young Jun Shim; Alona A. Merkulova; Sadiq Silbak; Yelenna Skomorovska-Prokvolit; David Midem; Sidney Ogolla; Bjoern B. Burckhardt; Tanja Gangnus; Julio Scharfstein; Celso Caruso-Neves; Owen J.T. McCarty; David Gailani; Michael Bader; Philip J. Rosenthal; Arlene E. Dent; Chris J. Janse; Keith R. McCrae; Ana Acacia de Sa Pinheiro; James W. Kazura; Alvin H. Schmaier

doi:10.1172/JCI202285

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by de Sa Pinheiro, A. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Teixeira, D. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Silva-Aguiar, R. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Shim, Y. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Merkulova, A. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Silbak, S. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Skomorovska-Prokvolit, Y. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Midem, D. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Ogolla, S. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Burckhardt, B. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Gangnus, T. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Scharfstein, J. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Caruso-Neves, C. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by McCarty, O. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Gailani, D. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Bader, M. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Rosenthal, P. in: PubMed | Google Scholar |

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Dent, A. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Janse, C. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by McCrae, K. in: PubMed | Google Scholar |

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by de Sa Pinheiro, A. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Kazura, J. in: PubMed | Google Scholar

¹Case Western Reserve University, Cleveland, United States of America

²Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Cleveland Clinic Foundation, Cleveland, United States of America

⁴Chulaimbo Sub-county Hospital, Kisuma, Kenya

⁵Kenya Medical Research Institute, Kisuma, Kenya

⁶Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Muenster, Germany

⁷Oregon Health & Science University, Portland, United States of America

⁸Vanderbilt University Medical Center, Nashville, United States of America

⁹Department of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany

¹⁰UCSF, San Francisco, United States of America

¹¹Leiden University Medical Center, Leiden, Netherlands

Find articles by Schmaier, A. in: PubMed | Google Scholar

Cerebral malaria (CM) from Plasmodium falciparum is a major cause of death in African children. Since bradykinin (BK) is a mediator of vasogenic edema, we hypothesized that it contributes to the pathogenesis of CM in Kenyan children and Plasmodium berghei ANKA (PbA) infected C57BL/6J mice in experimental cerebral malaria (ECM). Cleaved plasma high molecular weight kininogen (cHK) is a marker for BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA-infected mice with ECM had circulating cHK, elevated BK levels, and reduced HK and prekallikrein activity/antigen levels. HK null (Kng1^–/–), combined BK B1 and B2 receptor null (Bdkrb1^–/–/Bdkrb2^–/–), BK B2 (Bdkrb2^–/–) or BK B1 (Bdkrb1^–/–) receptor null mice were protected significantly from neurologic deterioration and brain edema compared to wild-type mice. F12^–/– mice were not protected from neurological deterioration. Prekallikrein null (Klkb1^–/–), prolylcarboxypeptidase hypomorphs (Prcp^gt/gt), and brain endothelial cell conditional knockout of PRCP (Prcp^fl/fl Cre) mice with ECM had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment in PbA-infected mice reversed neurologic deterioration and brain edema and significantly prolonged survival over artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.

Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria

Article tools

Metrics

Go to

Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria

Article tools

Metrics

Go to

Sign up for email alerts